This research program targets the synthesis of anticancer chemotherapeutics that are based on a class of natural product that inhibit histone deacetylase, which is a protein partly responsible for carcinogenesis. The proposed approach represents the first potential solid- phase method for generating the natural products in this class, one of which is already in phase II clinical trials for cancer treatment. Because it will ultimately be carried out on the solid-phase, the route described herein will provide fast, efficient access to a host of analogs (compounds similar to the natural products) that have not been available through any other reported synthetic approaches. Such analogs are expected to be a rich source of potential anticancer chemotherapeutics, and also embody a host of new structures for the study of how these molecules interact with their biological target proteins. Specifically, the outcomes of the proposed work include (1) a synthetic strategy for constructing two potential anticancer natural products;(2) a generally applicable protocol, based on this new synthetic strategy, for synthesizing not only the natural products, but a wider range of similar compounds than is currently available by any other established route towards such molecules;and (3) the synthesis of potential anticancer analogs of the natural products. The new synthetic methodology will provide access not only to the natural products, but to analogs containing components that have demonstrated importance for their biological activity. Using the methods proposed here, potential chemotherapeutics based on the target class of natural products will for the first time be accessible containing combinations of the best features of the most effective compounds previously reported. Moreover, this extremely flexible synthetic approach will also permit the construction of more creative, varied potential therapeutics than any established routes allow. Additionally, the proposed strategy will be particularly conducive to producing new compounds quickly, efficiently, and in parallel. Ultimately, large numbers of such compounds will therefore be accessible. Aside from leading to the next generation of potential anticancer therapeutics, along with the strategy to make countless others, this research program aims to educate and inspire the next generation of undergraduate students to enter scientific and health-related fields. PUBLIC HEALTH RELEVANCE: The major goal of the proposed work is the synthesis of a host of potential anticancer chemotherapeutics structurally similar to natural products that inhibit a protein partly responsible for carcinogenesis. The strategy used to assemble these molecules is significantly different from any other currently established method, and holds the promise of generating possible drug candidates that other methods have not been able to generate. In addition to providing new kinds of compounds, the proposed strategy will also be able to produce drug candidates more quickly than any other reported method.